Investigation of mutagenic roles of human LINE-1 retrotransposons in the pathogenesis of thyroid cancer

Thyroid cancer is the most common endocrine malignancy worldwide and ranks 9th among all new cancer cases. There has been a significant increase in the incidence of papillary thyroid carcinoma in the last 30 years. The incidence increase observed in TC-PTC (Tall Cell subtype Papillary Thyroid Carcinoma) is higher than in classical PTC (C-PTC). Therefore, identifying intracellular mutagenic factors affecting C-PTC and TC-PTC genomes is essential. It has been reported in the literature that human-specific LINE-1 (L1HS) retrotransposons play a role in the pathogenesis of many different cancer types; however, its role in the pathogenesis of thyroid cancer has not yet been discussed. Insertion profiles of the L1HS subfamily, the youngest / most active L1 retrotransposons, in DNAs isolated from tumour and control FFPE (Formalin-Fixed Paraffin-Embedded) tissue samples of histopathologically classified classical and TC-PTC patients were compared using TE-NGS (Transposable Element Next Generation Sequencing) method. L1HS insertions detected in both tumour and control tissues of C-PTC and TC-PTC samples were frequently localised in intronic regions. In the C-PTC and TC-PTC groups, L1HS insertions were found in many genes with mis-splicing mutations reported in cancers. The distribution of L1HS insertions in cancer-associated signalling pathways was found to be similar in both C-PTC and TC-PTC tumour tissue samples. Nevertheless, it was determined that L1HSs accumulated in the RTK-RAS signalling pathway proto-oncogenes in C-PTC control tissues, while in the TC-PTC, they were enriched in tumour suppressor genes of the Hippo signalling pathway. Regardless of tissue type, L1HS insertions seen in proto-oncogenes of the common signalling pathways in the groups were frequently localised within the intronic regions in the C-PTC group, and in the TC-PTC group, they mainly were at 5' flank regions, which could result in upregulation of the target proto-oncogenes. The results suggest that L1HS retrotransposons are active in both control and tumour tissue genomes of classical and tall cell subtype PTC and contribute to the background genetic instability required for neoplastic transformation. In addition, it is observed that the different L1HS insertion profiles of the C-PTC and TC-PTC groups may play a role in forming of unique histopathological and clinical results. The findings here reveal the importance of L1HS retrotransposons as a potential therapeutic target in thyroid cancer.